Study lends statins strong support but delivers a mixed message for antihypertensives

The widely reported results of HOPE-3 may bolster the case for primary prevention with statins and blood pressure drugs. But the trial also makes clear that the benefits, though real, are also modest, and are not evenly distributed between statins and antihypertensives.

Salim Yusuf, MD, DPhil, the principal investigator of HOPE-3, said that the trial does not support the case for universal primary prevention, or widespread use of a polypill, or the "put statins in the water" school of thought. Instead, said Yusuf, the trial supports a broader -- but by no means universal -- approach to primary prevention. Primary prevention with statins and antihypertensives will still need to be based on the assessment of individual patients and take into account their goals and desires.

The evidence was clearest in the cholesterol-lowering arm of the trial. For the intermediate risk population tested in HOPE-3, the trial added to the large amount of "clear evidence" showing the benefit of statins, said Yusuf. In sharp contrast, the blood pressure arm did not find any overall benefit for antihypertensive therapy, although there was a benefit in the prespecified subgroup with the highest blood pressure levels. The benefits of statins, on the other hand, did not vary by LDL level or level of risk.

"Statins work beautifully, resulting in a highly significant relative risk reduction of 25%," said Yusuf, who presented the findings at the American College of Cardiology meeting in Chicago and simultaneously online in the New England Journal of Medicine. Further, statins were "relatively safe," though there was a small excess in muscle pain, but not rhabdomyolysis, in the statin-treated group.

Results in the blood pressure arm were more complicated. Overall there was no significant difference in clinical outcomes, but there were significant differences based on the prespecified subgroups of blood pressure at baseline. Trial patients with the highest third of blood pressure at baseline (above 143 mm Hg) derived benefit from antihypertensive therapy. For patients in the middle third antihypertensive therapy had a neutral effect. For patients in the lowest third antihypertensive therapy had a harmful effect.

Yusuf says that the results suggest that all patients at intermediate risk should be eligible for statins, but antihypertensive therapy should only be offered to those with higher blood pressure levels. "The implications for practice are huge -- I think we certainly should consider using statins much more widely than we have used them thus far," he said, in a press release. "In particular for patients with hypertension, our study suggests you can essentially double the benefit of lowering blood pressure in hypertensives if you also lower cholesterol simultaneously."

HOPE After SPRINT

Yusuf said that the results of HOPE-3 are broadly consistent with recent primary prevention trials. An immediate question is how to view HOPE-3 in the wake of SPRINT, but it is important to recognize that the trials set out to answer very different questions in different populations.

"SPRINT targeted a high-risk population, we targeted intermediate risk," said Yusuf. In SPRINT, most patients were already receiving antihypertensive therapy, while patients in HOPE-3 were not receiving treatment prior to the trial. SPRINT and ACCORD suggest that high-risk patients can derive modest additional benefit from more aggressive treatment as opposed to less aggressive treatment. HOPE-3, on the other hand, shows that a simple primary prevention strategy, which does not require a great deal of dose titration or monitoring, can benefit the intermediate risk population.

By contrast, the aggressive approach in SPRINT was very intensive, and the patients had lots of side effects, said Yusuf. "You need to do it in treatment centers." This approach is not justifiable in lower-risk people, he said.

Asked to comment on the results, Sanjay Kaul, MD, MPH, of the Cedars-Sinai Heart Institute in Los Angeles, was far more impressed with the results in the statin arm than in the blood pressure arm. He considered the likelihood that it was lowering LDL, not the reduction in blood pressure, that chiefly produced the beneficial effect in the combined group that received both statin and antihypertensive therapy.

"So, how do we reconcile the null effects of BP lowering in HOPE-3 with the positive effects seen in SPRINT?" Kaul asked. "Is it the magnitude of BP lowering, the specific BP lowering agents, or the underlying population risk?" Kaul also warned that "positive subgroup results should always be interpreted with extreme caution" when the main outcome fails.

"Just when the whole world was trying to figure out what to do with the results of the SPRINT trial with various groups claiming that the target of <120 mm Hg should apply to a broader group of patients, the HOPE-3 BP trial brings this train to a screeching halt. One is left to wonder if the results would have been any different if a diuretic with a proven track record at reducing events such as chlorthalidone were to be used (as was encouraged in SPRINT) instead of hydrochlorothiazide, which in low dose has never shown to reduce morbidity and mortality in hypertension. Nevertheless, a good take home lesson is not to extrapolate results of a trial beyond the patient population enrolled or the treatments tested."

In an accompanying editorial in the New England Journal of Medicine, William Cushman, MD, and David Goff, MD, speculated that higher doses of the antihypertensive drugs, or the use of chlorthalidone (Thalitone) instead of hydrochlorothiazide, might have led to a significant reduction in cardiovascular events.

What Does HOPE-3 Mean in the Real World?

Yusuf acknowledged the criticism that focusing on relative risk reduction can hide small absolute differences in risk. "Absolute risk reduction is always an issue with primary prevention."

But he also pointed out that, because of the short follow-up in trials, the probable lifetime benefit of continuous treatment is much larger than the benefit observed during trials. Another important factor is that trials don't focus on recurrent events, yet these are often clinically quite important. Yusuf said that trial participants will be followed for another 3 to 5 years, thereby perhaps helping to shed additional light on this question.

I asked Yusuf whether it was better to spend money and resources on primary prevention measures or whether resources should be shifted to other public health measures. He acknowledged the importance of public health measures but pointed out that with the exception of smoking and, perhaps, exercise, the evidence base for most public health campaigns is mixed. He said the discussions around diet and salt are good examples of why we need to focus on measures with solid supporting evidence.

Yusuf said that the size of the intermediate-risk population eligible for primary prevention is enormous. He estimated that three-quarters of men over the age of 55 and women over the age of 60 would be eligible, based on HOPE-3 criteria.

Richard Lehman, a retired U.K. general practitioner who has thought extensively about primary prevention and patient communication, said that the HOPE-3 results "are an enormous step forward in helping millions of people to decide whether or not to take statins and/or blood pressure lowering drugs. At last we are able to cite reliable ball-park figures from a representative population at intermediate risk of cardiovascular disease. They confirm that statins reduce risk by about a quarter, whatever the starting point, whereas for blood pressure lowering below a systolic of 143, this does not appear to be true over 5 to 6 years. However, it may be that BP lowering has benefits over a longer period of time, particularly for the risk of heart failure."

Lehman wants to see the results made available to patients: "What we urgently need now are well-designed, user-friendly infographics to help people decide for themselves."

Yusuf reported grant support from the Canadian Institutes of Health Research and AstraZeneca during the conduct of the study; grant support from AstraZeneca, Novartis, Bristol-Myers Squibb, and Cadila Pharma, and grant support, personal fees, and non-financial support from Bayer outside the submitted work.

Cushman reported grant support from Merck and Eli Lilly outside the submitted work. He is also an uncompensated member of the steering committee for the Takeda-sponsored EXAMINE diabetes CV outcome trial, and he provides uncompensated consulting to Takeda related to hypertension clinical trials.